Plasma proteomics profiling of 87 phospholamban R14del carriers identified 5 distinct clusters, revealing an asymptomatic subgroup at high risk for disease progression.
Cohort (n=87)
Can plasma proteomics stratification identify phospholamban R14del carriers at risk for disease progression?
Molecular profiling of phospholamban R14del carriers identifies distinct subgroups, enabling early identification of asymptomatic individuals at high risk for cardiomyopathy progression.
Abstract Aims Incomplete penetrance is common in genetic cardiomyopathy, but poorly understood. Here, we investigate the circulating molecular signature in a cohort of patients with one specific phospholamban (PLN) p.Arg14del (R14del, R14Δ/+) mutation underlying R14Δ/+ cardiomyopathy and its association with disease variability and progression. Methods and Results Targeted proteomics, metabolomics and lipidomics was performed on plasma from 87 R14Δ/+ carriers across the disease spectrum. Unsupervised clustering of plasma proteomics classified R14Δ/+ carriers into clusters, which were evaluated using clinical data, including HF symptoms, echocardiographic parameters and clinical follow-up. Metabolomics and lipidomics data were integrated. Five clusters of R14Δ/+ carriers were identified based on plasma proteomics (N=2616 proteins). Clusters 3, 4 and 5 were enriched for higher NT-proBNP levels, and lower left ventricular ejection fraction (LVEF), compared to clusters 1 and 2. Ninety-six out of 148 metabolites were differentially expressed across the clusters. Levels of symmetric dimethylarginine (SDMA), N-acetyl aspartate, cis-aconitic acid, S-adenosyl-L-methionine (SAMe), acadesine (AICAR) and succinate were elevated in disease condition clusters 3, 4 and 5. Levels of energy metabolism-related metabolites (i.e. ATP and nicotinamide), were elevated in clusters 1, 3 and 4, and correlated strongly with apoptosis markers, indicating ongoing cardiac damage. Cluster 1 and 2 represent seemingly asymptomatic R14Δ/+ carriers with cluster 1 suspected at risk for cardiac damage due to elevated apoptosis markers. Cluster 3 shows an intermediate phenotype and cluster 4 and 5 consist of R14Δ/+ carriers with end-stage HF. Clinical follow-up confirmed cluster 1 at risk for R14Δ/+ cardiomyopathy progression due to increased adverse events (HF hospitalization, all-cause mortality or cardiac device implantation). Conclusion Molecular profiling of R14Δ/+ carriers reveals subgroups with very distinct risk profiles. Early markers of cardiac damage suggest that stratification may enable timely identification of high-risk individuals and improve understanding of disease variability.
Deiman et al. (Thu,) conducted a cohort in Phospholamban (PLN) p.Arg14del (R14del) cardiomyopathy (n=87). Plasma proteomics, metabolomics, and lipidomics profiling was evaluated on Disease progression (heart failure hospitalization, all-cause mortality, or cardiac device implantation). Plasma proteomics profiling of 87 phospholamban R14del carriers identified 5 distinct clusters, revealing an asymptomatic subgroup at high risk for disease progression.